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Medical Forum / General / Vision / December 2007Carotenoid Transport into the RPE
Fair warning: I've had very little time(<2 weeks) to research and think about this so don't be surprised if I am blundering along here. I'm trying to track down the following: Whether or not there are differing transporters into the rod and cone cells, and the RPE cells, for the pro-vitamin A carotenoids\retinoids and the non-pro ones, lutein and zeaxanthin. Can anyone help??? The retinoids go off into the visual cycle, in STGD(stargardt) there is an accmulution of retinoids in both the ROS and in the lipofuscin in the RPE. There is also some evidence to suggest a lack of L and Z in the RPE for STGD patients. I suspect that the ABCA4 product, Rim protein, may have a preferential transport of retinoid products, particularly those with PE component, but I'm beginning to wonder if there if there is another transport function here, that of L and Z into the RPE, being depleted either by the lipofuscin products, which clearly have a significant retinoid component, or if the Rim protein also serves a role of transporting L and Z into the RPE. The problem is that Rim protein, as currently understood, appears to be a specific product of the rod and cone cells. The current paradigm for STGD goes like this: The Rim protein(protein from ABCA4) is dysfunctional, it transports shed ROS to the RPE for "reprocessing" and the product of the same is purportly then transported back to the ROS. Yet if Rim protein is a product of rod and cone cells, and in STGD the lipofuscin is present in the RPE, not the rods and cones, and if RPE cells first die, this seemingly precipitating photoreceptor death, then shouldn't we expect to see aggregations primarily in the rods and cones, not the RPE? It don't make sense. It might go like this: the Rim protein has two ATP binding clefts, the transport across cell membranes is ATP dependent, so perhaps the relevant alleles impact on ATP capture or hydrolysis. So the ROS fragments are transported to a RPE cd36 receptor where they can be scavenged, but it may be the case that further ATP is required for transport to the lysosomes within the RPE to initiate degradation. I am too ignorant about biochemistry to know whether or not ATP can be transported through a cell membrane via an ABC transporter and even if that is possible do lysosomes require ATP from this source or are these ATP independent processes. We're awating genetic testing results but for now I'm assuming ATP involvement because there is good evidence to suggest that enhancing mitochondrial function can not only prevent aggregation but in AMD at least even reduce pre-existing aggregates. It may not even be an ATP issue, allele variation may be related to the tranporter segment that binds the retinoid proteins. The incomplete transport may then allow oxidation via light which exposes hydrophobic cores, allowing aggregation, preventing adequate transport, perhaps even "clogging" the RPE cd36 scavenger receptor, so the process goes downhill from there. Fascinating problem, very f.cking difficult, driving me nuts. So then, can anyone point me to a good article on how the ROS is constructed, what are its constitutents, and are L and Z present in the photoreceptor cells or are L and Z very much located in the RPE? Sort of an academic exercise, asked by friends to help with their daughter recently diagnosed with STGD. My role there mostly over but now I'm perservating on the bloody thing. See, a little brain damage goes a long way ... to Hell and back. Hey Glen, if you got this far, I really could do with a lesson in the finer subtleties of statistical analysis! I suspect that after this I'm also going to need a DRD2 antagonist .... Someone take these dreams away .... they keep calling me(Dead Souls, Joy Division) John. > Fair warning: I've had very little time(<2 weeks) to research and think > about this so don't be surprised if I am blundering along here. [quoted text clipped - 61 lines] > with a lesson in the finer subtleties of statistical analysis! I suspect > that after this I'm also going to need a DRD2 antagonist .... Hi John. I'm not sure I can help the sort of subtleties you might have in mind. Remember, behavior analysts eschew the use of statistics but, of course, I published in journals that require inferential statistics so I have used them - usually repeated measures ANOVA. I know that you were probably just making conversation, but far be it from me to pass up a chance to bad mouth inferential statistics. One of the weird things about p-values is that if you reject the null-hypothesis, the p-value becomes, in a sense, meaningless! This is because a p-value gives the probability of obtaining differences between two groups that are equal to or more extreme than what you obtained GIVEN THAT THE NULL-HYPOTHESIS IS TRUE! But if you reject the null-hypothesis on the basis of the p-value, what is the quantitative meaning of the p-value? Many people think that the p-value "gives the likelihood that the data you obtained are due to chance," but that is the equivalent of saying that it is the probability that the null-hypothesis is true given the data. But, as I have just described, that is not what a p-value gives - it gives the probability of obtaining the data given that the null hypothesis is true! This does not mean that a small p-value should not cause you to reject the null-hypothesis, but as I said in a previous post, rejecting the null hypothesis becomes increasingly likely as a function of sample size! I am increasingly becoming enamored with Beyesian statistics thanks to the unfortunately-absent Michael Olea. That guy is really smart (but I think praise makes him somewhat uncomfortable). Beyesian statistics do, in fact, give you the p that your hypothesis is true given the data. Another thing that people think is that, if the p-value is really small, repeating the experiment is likely to reproduce the results of the first, but this is not true, as far as I can see. The only way to show that a finding is reliable is to replicate it. But a lot of journals discourage the submission of experiments that solely function as replications! Anyhow...speaking of smart, you should be proud of your scientific abilities. BTW, I don't think that I ever saw the abbreviation DRD2 and had to Google it. I suspected it was a DAergic D2. Do you think you need a D2 antagonist for migraine or psychosis? I know what you mean though - I have thought about certain topics on and off for decades, and sometimes cannot abandon the problem for months at a time. Good luck in your endeavors, Glen > Someone take these dreams away .... they keep calling me(Dead Souls, Joy > Division) > > John. >> Fair warning: I've had very little time(<2 weeks) to research and think >> about this so don't be surprised if I am blundering along here. [quoted text clipped - 69 lines] > probably just making conversation, but far be it from me to pass up a > chance to bad mouth inferential statistics. Certainly not Glen, I really have to get on top of this because a great many epidemiological studies I've looked at come up with some weird and often contradictory assertions. I suspect people are placing far too much significance of p values, and RRs seem to be all over the place. Beta carotene is a real confounder here, the cellular studies clearly indicate that in Stargardts, and possibly even Adult macular degeneration, high beta carotene is a risk. Yet the epidemiological studies are contradictory on this point, so now I'm trying to convince some clinicians not to boost the child's beta carotene, there is absolutely no biochemical or cellular logic for this. It isn't just a matter of the mathematics, it also a matter of sampling. For me at least, there is something very suspicious about how conclusions can change so markedly just because 'n' changes. It seems to me statistics is a useful but still blunt instrument and too often people let statistical algorithms get in the way of logic. Even what you have said below is a relief, it suggests that I thinking in the right direction. Not the first time this has happened to me, perhaps I should be more confident in my thinking because often it seems my doubts about my logic should be directed at the logic of others. Aaah even in this iconoclast the Authority Fallacy holds some sway .... Thanks, you have always been very helpful and it is great to see someone of your intellectual and professional stature proffering their expertise, this quality seems to be increasingly rare in the world these days. DRD2 - just me playing around with perservation, the linkage between psychosis and intellectual creativity, and the often frequent need, when approaching problems of these complexity, to be obsessed to the point of near madness in order to adequately think about it. I've worked my guts out on this because my friends have a great 11 year old girl and stargardts moves so quickly that time truly is of the essence here. My problem in these days, and my principle area of interest, neurodegeneration, is I really need a lab ... . Yes, real shame Olea is away. Haven't seem him for months but he always has good input. Be well my friend, John. One of the weird things about p-values > is that if you reject the null-hypothesis, the p-value becomes, in a > sense, meaningless! This is because a p-value gives the probability of [quoted text clipped - 33 lines] >> >> John. (trim) >Hi John. I'm not sure I can help the sort of subtleties you might have in >mind. Remember, behavior analysts eschew the use of statistics but, of [quoted text clipped - 24 lines] >a finding is reliable is to replicate it. But a lot of journals discourage >the submission of experiments that solely function as replications! Confidence intervals are only a little further into the statistics books than p-values and are a good deal more illuminating. If the p-value would reject the null hypothesis then the confidence interval gives you a measure of how far away from the null hypothesis you can plausibly be. If the p-value would not reject the null hypothesis you get a measure of how big an effect there might be hiding under the noise. One useful application of confidence intervals is to run an experiment with the intention of dismissing some proposed effect - you can't prove a negative, but you could come up with a small confidence interval around zero and say that any possible effect must be negligible. This would be a reason for doing experiments on folk wisdom preventative measures for eyesight even if you didn't believe them; you could advance the state of knowledge by running a statistically rigorous experiment to dismiss them once and for all. A related (not exactly identical) application is testing for bio-equivalence, where a drug manufacturer has the goal of showing that there is no practical difference between two drugs from different production processes. Note that some of the people bad-mouthing p-values (e.g. various psychologists) are suggesting confidence intervals as at least one possible replacement. If you assume enough you can get some sort of link between p-values and reproducibility, but the figures aren't very encouraging, largely because a lot of statistics is done with the minimum possible sample size, if not smaller. Suppose that you have a two-tailed p-value of 0.001 for a simple test of a normally distributed value with known unit variance. This means that the observed deviation was about 3.29 sigma. The difference between two variables with unit variance has standard deviation sqrt(2). With probability 90% the replicate is no more than 1.28 * sqrt(2) less encouraging than the original, which is 1.81, so with probability 90% the replicate comes up with 1.48 sigma or better, but 1.48 sigma is a 2-tailed value of 13.9% or so - n.s. If the original p-value was 1.0E-6 then sigma increases to 4.89 sigma, so with probability 90% or more we get 3.08 sigma or better, which is a 2-tailed significance of p = 0.002.  SignatureA.G.McDowell > (trim) >>> [quoted text clipped - 13 lines] > the state of knowledge by running a statistically rigorous experiment to > dismiss them once and for all. snip Thanks for your input. The statistical anomalies are one problem but during the the course of this rushed analysis I have come to despair of what typically passes as health news. Infuriartingly there are mountains of websites citing a study or two and then claiming the same proves that substance A or B is the way to go re this or that health related matter. Health reports are clear evidence of sick minds. I have developed an approach which helps address this issue but it is very taxing and beyond most people. I would have to spend the rest of my life studying health related issues re nutrition and still only cover a small proportion. My approach is simply(!) to address the relevant issue at multiple levels of analysis. So I look for synergy between epidemiological(try to avoid retrospective studies but cannot always be done), physiological studies, cellular studies, and to a much lesser extent biochemistry studies. It is the only way I can think of that allows me any reasonable degree of confidence in these investigations. Obviously this is a far cry from a typical gold standard of clinical practice, The Cochrane Reviews. I'm even more cynical about meta analyses ... There is a clear antagonism between conventional and alternative medicine which is another bugabear confounder. Obviously there are "folk wisdom" remedies that can have considerable value, I've used some myself and to very good effect. Unfortunately I intuit a bias against the same in US studies, a bias towards the same in some European studies, and in China they just love Chinese traditional medicine ... . This is a real sh.t, it just makes it all that much harder. Fortunately there are sources around that make strenuous efforts to be objective. In general though I regard much of what passes as "health new" as deepy misleading and hopelessly simplistic. A few examples: Selenium. One doctor said to me that I had fallen for the selenium myth. This dumb dick obviously had read a paper in over 20 years. The RDA in Australia for Se is 65 ug, yet longitudinal studies indicate that 200ug supplementation halved the rates of many major cancers, and some say the upper safe limit is 400ug. Australia has very low Se in the soils, so much so that when cattle were first introduced here Se had to be added to their feed. However if the cattle are feeding near coal power stations, which can release lots of Se, they can experience Se toxicity. Only recently has Se been added back into multi vits and the reason for this is that when the value of Se was first established the dumbass anal health nuts took too much and so had Se toxicity. So the conventional recommendation for Se is way too low and needs to be country, perhaps even geographic region specific. Macular Degeneration The typical advice is to eat lots of carotenoids. Generally okay except these are stored in the liver, fat soluble, and the true protective value is found in two specific carotenoids, lutein and zeaxanthin. Pro vitamin A carotenoids go directly into the vision cycle and can be reprocessed through the RPE, generally it is extremely difficult to have a deficiency of pro vitamin A but macular protection, which is very important for anyone intending to live past 70, is more contingent on lutein and zeaxanthin intake than beta carotene. Some studies even demonstrate that too much beta carotene increases the risk of Age related macular degeneration and this does have concordance with some cellular and biochemical studies. It may even have concordance at a physiological level because the gut transporters for carotenoids may prefer pro vitamin A's over L and Z, hence it is wise to try focus on those foods which specifically increase the intake of the latter, rather than just pumping up on vitamin A in general. Only last night I found a few studies indicating that lutein and zeaxanthin are often transported by HDL and vLDL. This may be misleading though, it could be that being fat soluble the L and Z were bound to the fats being transported, not HDL and vLDL specifically. In relation to Stargardts there is even strong evidence to suggest that keeping pro vitamin A carotenoid intake low is a good idea. My friends took their daughter off to a naturopath who immediately prescribed massive Vit A dosing(perhaps even high enough to cause liver toxicity). Naturally I hit the roof and wanted to tear down that naturopaths shingle. RDAs in general RDAs are a joke, individual nutrition requirements can vary many fold and even vary depending on overall health. RDAs are at best a broad guide but RDAs are really about preventing deficiency related pathologies not optimising health. Typically, even for lipid soluble nutrients, one can take many times the RDA without ill effect, though I'd be cautious in pushing that barrow too far. Mega dosing of vitamin C can be dangerous, it may even induce extensive oxidation. Yet the megadosing C idea was originally promulgated by Linus Pauling, the only person to win the Nobel Twice. Meg dosing of Vit A, if sustained, may not only be a risk factor for macular degeneration, there is emerging evidence it may induce osteoporosis. Excessive iron intake is just plain dumb, if you have any inflammatory condition reducing iron intake, even phlebotomy, can reduce inflammation(there are also a number of studies that offer support for this). That's why you rarely see iron in multi vits these days, or at least very low levels of the same. Yet I can remember 20 years ago ... . Calcium from milk? That is also problematic. -------------- I'll stop here ... it just goes on and on and on. It's a real sh.t. The irony being that the single best thing we do for our health is learn to stay little hungry. Caloric restriction(still problems here), weekly fasting, alternative dietary regimes, all ideas you won't find in the health shops or the doctors'surgeries or the naturopaths, are far wiser approaches than salivating over the latest "health news". Hmmm, maybe I should write a book about all the bullshit that passes as Health News. So thanks for your input. As you can see that statistical issue is just the tip of an incredibly deceptive ice berg. Now that I'm home from work and got that off my chest, I can start working again ... John. John, If you have some time left over, you may want to look at the level of zinc recommended for macular degeneration. The AREDS2 (very large) study set the level at 80mg. But a recent (very small) study says they have found zinc as a constituent of drusen. Now everyone is backing off of the 80mg. The power of a very small study. Don W. > John, > [quoted text clipped - 5 lines] > > Don W. Thanks Don, The Blue Mountains study(large) found an RR for high zinc of .56 from top to lowest quintile, hence a strong protective effect. Damn. Yes, have been looking at the AREDS studies. A2E is and R-PE compounds are big constitutents of drusen and lipofuscin, a retinol binding protein inhibitor 9(4HPR but very toxic) markedly reduced lipofuscin aggregation, and biochemistry of A2E and retinoid related proteins indicate that when oxidised, as these easily are in the retina, do become cytotoxic. So the evidence for reducing pro-vit A's is quite strong across a number of levels. Yet almost invariably people are told to eat lots of vit a rich food, even though there are now a number of studies suggesting that chronic high intake of the same can have a number of risks including mac degen, liver damage, osteoporosis and even a hint of increased cancer risk. Now to zinc: There is the suggestion zinc is required for carotenoid transport into the retina. Zinc is an important component of Cu\Zn SOD, a critical cytoplasmic endogenous antioxidant. some say high zinc precludes Cu intake. But high Cu intake can make you psychotic and in Wilson's Disease, where cu cannot be eliminated, there is a noticeable ring in the outer iris arising from Cu accumulation. At high levels both zn and cu are dangerous, this is true of all heavy metals. Some balancing act eh? In a way same problem as pro vit A carotenoids, a matter of balance but how to determine the right balance for each person. Is the zinc issue one of guilt by association? Has anyone tried chelation therapies for reductions in oxidation in the retina?(strong odds this would work for Fe, which is present in damaged neurons and retina) Do we need to contrast high zn and low carotenoid vs low zn and high carotenoid? PS: One of the more promising aspects I have come across is strong evidence that these aggregations can be reduced(note: not rate of accumulation but actual real reductions in total drusen) by mitochondrial function enhancement(using what is essentially a "folk wisdom" approach), bright light avoidance, and keeping away from UV light and blue light. There's a rub, wear the sunnies to protect the eyes but keep up the vit D production via UV(much better than pills, most of which are useless re vit D uptake), and vitamin D has strong anti cancer properties and anti-inflammatory properties. Ah ya just can't bloody win, one way or the other the universe is gonna do us in .... . Me go mad now, time to come up with my own Theory of Everything and annoy you lot endlessly until they take me away hey hey ... . John. John, Since I am at the AR end of ARMD I cannot comment too much on the Stargardt's problem. Except to say that I think your efforts are quite noble to help that 11 year old. I can only imagine the impact on the parents. Good luck with your efforts. That small study on zinc and drusen appeared in Exp Eye Res 2007 Apr by Lengyel, as you probably know. Oh, have not read (or heard of) the "reduction of total drusen" by the "folk wisdom" approach (blueblockers). The reduction part threw me. Where did you pick that up? One side effect of this thread is it has given me a better heads up on the biophysics of the whole (hole??) darn problem. Thanks. Don W. Hey Don, With regard to reduction look up "phototrop". This is just a compound of omega 3's, acetyl l carnitine, and coq10. See abstract below. (They should have added lipoic acid in the R conformation!) The common perception is that the aggregations are gradually built up but I have found sufficient evidence to argue against that. It appears these aggregations are being dispensed with via lysosome degradation and that the problem is the rate of degradation vs. accumulation. This has very important implications for a wide variety of retinal conditions because drusen and in particular lipofuscin appear to be the big problem. There are a few other avenues to explore, like periodic resting of the retinas through "palming", an idea originally promulgated by a strange bod, William Bates. This may be of benefit re juvenile mac degen but I'm doubtful re age related. You may want to consider not only UV filtering glasses but also blue light filtering glasses, blue light also oxidises various retinoid compounds in the eye and this seems to impede phagocytosis. Get used to dim light, even indoors, that idea that dim light causes eyestrain while reading is nonsense. I have read one study where it was found there was more retinal damage during those periods when circadian time would dictate an absence of light(for humans, at night). Very odd finding but I've read other studies on circadian dynamics which indicate circadian rhythms can have profound effects on the impact of drugs etc. Trying using a sleep mask so as to maximises circadian stability and melatonin levels. Melatonin is very protective of neurons but declines markedly with age. Supplements are available but much caution needed here, can make you very drowsy. I have read a study showing good increases in melatonin production via acupuncture. Yes, acupuncture can help in some conditions and no it is not the placebo effect. Even if it was is that a bad thing? Watch the beta carotene, focus on lutein and zeaxanthin. The studies don't really support this selenium supplements are worthy of consideration, also keep your iron levels low. Generally, keep fat levels low, plenty of exercise to stimulate blood flow, and consider Ginkgo, some trials suggest a benefit but NOT if you have wet AMD. Still not sure about ginkgo, lots of conflicting results but it does preserve ATP production and my suspicion is that this is very important to maintain both phagocytosis and lysosome functions. Whether or not I can help the girl and her parents is very much a gamble. A great deal depends on the allele she is carrying for ABCA4. A more deleterious type makes all my work largely in vain. Genetic testing is under way. I am doubtful that my efforts wil yield any significant benefit but its early days yet. I have, or at least think I have, very much nailed down the problem to a rather discrete level, that gives me some hope. There are also some very promising gene therapies currently in clinical trials on humans, so trying to slow progression is worth the effort because if these therapies work any reduction in pathology progression can potentially make a huge difference to the girl's vision in adulthood. Good luck in your endeavours. John. 4/11/2007 17:13 Ophthalmologica. 2005 May-Jun;219(3):154-66.Click here to read Links Improvement of visual functions and fundus alterations in early age-related macular degeneration treated with a combination of acetyl-L-carnitine, n-3 fatty acids, and coenzyme Q10. Feher J, Kovacs B, Kovacs I, Schveoller M, Papale A, Balacco Gabrieli C. Ophthalmic Neuroscience Program, Department of Ophthalmology, University of Rome 'La Sapienza', Rome, Italy. The aim of this randomized, double-blind, placebo-controlled clinical trial was to determine the efficacy of a combination of acetyl-L-carnitine, n-3 fatty acids, and coenzyme Q10 (Phototrop) on the visual functions and fundus alterations in early age-related macular degeneration (AMD). One hundred and six patients with a clinical diagnosis of early AMD were randomized to the treated or control groups. The primary efficacy variable was the change in the visual field mean defect (VFMD) from baseline to 12 months of treatment, with secondary efficacy parameters: visual acuity (Snellen chart and ETDRS chart), foveal sensitivity as measured by perimetry, and fundus alterations as evaluated according to the criteria of the International Classification and Grading System for AMD. The mean change in all four parameters of visual functions showed significant improvement in the treated group by the end of the study period. In addition, in the treated group only 1 out of 48 cases (2%) while in the placebo group 9 out of 53 (17%) showed clinically significant (>2.0 dB) worsening in VFMD (p = 0.006, odds ratio: 10.93). Decrease in drusen-covered area of treated eyes was also statistically significant as compared to placebo when either the most affected eyes (p = 0.045) or the less affected eyes (p = 0.017) were considered. These findings strongly suggested that an appropriate combination of compounds which affect mitochondrial lipid metabolism, may improve and subsequently stabilize visual functions, and it may also improve fundus alterations in patients affected by early AMD. PMID: 15947501 [PubMed - indexed for MEDLINE] > John, > [quoted text clipped - 14 lines] > > Don W. Don, This also looks very promising, just came across it. NAC is a popular antioxidant. There is a recent warning about it though but I can't find it. However a very quick look suggests it shows promise as an adjunct treatment across a wide range of pathologies. Recent warning is below but it is hardly a serious one. Typical of the USA, will do anything to attack the supplement industry. If NAC were such a problem as outlined here it would have become obvious a long time ago. Possibly an issue for those with CHD, high blood pressure, or over 60 years of age but your doctor could probably monitor for this condition. I can't explain this simply but degradation failure was precisely my target this afternoon, after a week thinking about it .... No point improving phagocytosis without degradation so as the authors note this represents a new strategy for AMD, and Stargardts for that matter. : Klin Monatsbl Augenheilkd. 2007 Jul;224(7):580-4.Click here to read Links [N-acetylcysteine improves lysosomal function and enhances the degradation of photoreceptor outer segments in cultured RPE cells] [Article in German] Schütt F, Völcker HE, Dithmar S. Universitätsaugenklinik Heidelberg, Heidelberg [N-acetylcysteine improves lysosomal function and enhances the degradation of photoreceptor outer segments in cultured RPE cells] [Article in German] Universitätsaugenklinik Heidelberg, Heidelberg, Germany. BACKGROUND: In the retinal pigment epithelium (RPE) lipofuscin granules accumulate with age in the lysosomal compartment mainly as a byproduct of constant phagocytosis of oxidized membranous discs shed from photoreceptor outer segments. Antioxidative defiency and prooxidative conditions in the RPE play a key role in the pathogenesis of RPE dysfunction and macular degenerations such as ARMD. In human RPE cell cultures we investigated the antioxidative effect of N-acetylcysteine (ACC) on lysosomal functions. METHODS: Primary human RPE cell cultures were loaded with regular or oxidized human and porcine rod outer segments (ROS) and treated with ACC. Lysosomal volume and accumulation of autofluorescent material was measured using [14C] methylamine accumulation and FACS analysis. The regulation pattern of lysosomal proteins were investigated by proteome analysis. RESULTS: ACC reduced total lysosomal volume in control, ROS and oxidized ROS fed RPE cells. After ROS incubation increased accumulation of autofluorescent material was measured. ACC treatment decreased intracellular accumulation. Furthermore, incubation with ACC leads to a general down regulation of lysosomal proteins. CONCLUSION: In our cell culture model of ROS fed RPE cells simulating aged RPE ACC improves lysosomal volume and metabolism. Therefore ACC may represent a new prophylactic and causal treatment option for AMD. PMID: 17657692 [PubMed - indexed for MEDLINE] 7/09/2007 13:22 A Type Of Antioxidant May Not Be As Safe As Once Thought Certain preparations taken to enhance athletic performance or stave off disease contain an antioxidant that could cause harm. According to new research at the University of Virginia Health System, N-acetylcysteine (NAC), an antioxidant commonly used in nutritional and body building supplements, can form a red blood cell derived molecule that makes blood vessels think they are not getting enough oxygen. This leads to pulmonary arterial hypertension (PAH), a serious condition characterized by high blood pressure in the arteries that carry blood to the lungs. The results appear in the September issue of the Journal of Clinical Investigation. "NAC fools the body into thinking that it has an oxygen shortage," said Dr. Ben Gaston, UVa Children's Hospital pediatrician and researcher who led the study. "We found that an NAC product formed by red blood cells, know as a nitrosothiol, bypasses the normal regulation of oxygen sensing. It tells the arteries in the lung to 'remodel'; they become narrow, increasing the blood pressure in the lungs and causing the right side of the heart to swell." Gaston notes that this is an entirely new understanding of the way oxygen is sensed by the body. The body responds to nitrosothiols, which are made when a decreased amount of oxygen is being carried by red blood cells; the response is not to the amount of oxygen dissolved in blood. He says that this pathway was designed much more elegantly than anyone had previously imagined. "We were really surprised", he said. The research team administered both NAC and nitrosothiols to mice for three weeks. The NAC was converted by red blood cells into the nitrosothiol, S-nitroso-N-acetylcysteine (SNOAC). The normal mice that received NAC and SNOAC developed PAH. Mice missing an enzyme known as endothelial nitric oxide synthase did not convert NAC to SNOAC, and were protected from the adverse effects of NAC, but not SNOAC. This suggests that NAC must be converted to SNOAC to cause PAH. Could regular use of NAC produce the same effects in humans? The next step is to determine a threshold past which antioxidant use becomes detrimental to heart or lung function, according to Dr. Lisa Palmer, co-researcher of the study. "The more we understand about complexities in humans, the more we need to be aware of chemical reactions in the body," said Palmer. According to Gaston and Palmer, NAC is being tested in clinical trials for patients with cystic fibrosis as well as other conditions; and clinical trials with nitrosothiols are being planned. These results, Palmer says, should motivate researchers to check their patients for PAH. The results also open up a range of possibilities in treating PAH. Palmer added that the signaling process could be restorative and healing if they figured out how to keep NAC from fooling the body. "From here we could devise new ways for sensing hypoxia or we could in theory modify signaling to treat PAH," Palmer said. > John, > [quoted text clipped - 14 lines] > > Don W. John, I had thought that since Stargardt's and ARMD could both benefit from anything that would increase the macular pigment (MP), that is would be nice to measure how well taking lutein/zeaxantan affects the macula. First measure the improvement (increase) and then see how well this affects acuity. I had wondered before if increases in MP would directly affect acuity. This paper answers this question somewhat. This paper was presented at ARVO 2006. Did not like the comment that central vision was not changed. Oh and MP density correlated with OCT retinal thickness, as mentioned in the original ARVO abstract. Have other comments, but just found original abstract in my Misc file. Don W. ***** Investigative Ophthalmology and Visual Science. 2007;48:1319-1329.) © 2007 by The Association for Research in Vision and Ophthalmology, Inc. Articles by Jacobson, S. G. Macular Pigment and Lutein Supplementation in ABCA4-Associated Retinal Degenerations Tomas S. Aleman,1 Artur V. Cideciyan,1 Elizabeth A. M. Windsor,1 Sharon B. Schwartz,1 Malgorzata Swider,1 John D. Chico,1 Alexander Sumaroka,1 Alexander Y. Pantelyat,1 Keith G. Duncan,2 Leigh M. Gardner,1 Jessica M. Emmons,1 Janet D. Steinberg,1 Edwin M. Stone,3 and Samuel G. Jacobson1 1From the Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania; the 2Department of Ophthalmology, University of California, San Francisco, California; and the 3Department of Ophthalmology, University of Iowa Carver College of Medicine, Iowa City, Iowa. PURPOSE. To determine macular pigment (MP) optical density (OD) in patients with ABCA4-associated retinal degenerations (ABCA4-RD) and the response of MP and vision to supplementation with lutein. METHODS. Patients with Stargardt disease or cone-rod dystrophy and known or suspected disease-causing mutations in the ABCA4 gene were included. All patients had foveal fixation. MPOD profiles were measured with heterochromatic flicker photometry. Serum carotenoids, visual acuity, foveal sensitivity, and retinal thickness were quantified. Changes in MPOD and central vision were determined in a subset of patients receiving oral supplementation with lutein for 6 months. RESULTS. MPOD in patients ranged from normal to markedly abnormal. As a group, patients with ABCA4-RD had reduced foveal MPOD, and there was a strong correlation with retinal thickness. Average foveal tissue concentration of MP, estimated by dividing MPOD by retinal thickness, was normal in patients, whereas serum concentration of lutein and zeaxanthin was significantly lower than normal. After oral lutein supplementation for 6 months, 91% of the patients showed significant increases in serum lutein, and 63% of the patients' eyes showed a significant augmentation in MPOD. The retinal responders tended to be female and to have lower serum lutein and zeaxanthin, lower MPOD, and greater retinal thickness at baseline. Responding eyes had significantly lower baseline MP concentration than did nonresponding eyes. Central vision was unchanged after the period of supplementation. CONCLUSIONS. MP is strongly affected by the stage of ABCA4 disease leading to abnormal foveal architecture. MP could be augmented by supplemental lutein in some patients. There was no change in central vision after 6 months of lutein supplementation. Long-term influences of this supplement on the natural history of these macular degenerations require further study Thanks Don, Have read this one. They key phrase is Responding eyes had significantly lower baseline MP concentration than did nonresponding eyes. Central vision was unchanged after the period of supplementation. --- Once the photoreceptors are gone there aint no turning back, hence visual recovery is rare. Where it does occur it probably relates to neurons that are on the way out hence not working probably and subsequently saved by the therapy. On a positive note though, there are some very promising clinical trials on gene and stem cell therapies. Neurons are clever little bastards, just place ém in the right environment and they often morph into the right form and function. Amazing stuff. Those odd Aussies have already created cochlear implants that are getting better by the year and there is no intrinsic reason why the same won't happen with vision. In a sense it already has, artificial retinas have been implanted in humans and are, albeit in a very limited sense, functional. John. > John, > [quoted text clipped - 62 lines] > on the natural history of these macular degenerations require further > study John, Noticed (after I sent the last note) that a/the LAST study (Lutein antioxidant supplementation 2004 study) also tied in macular pigment increases with lutein intake _and_ the acuity increases. And just recently (as far as my (this early am) searches) there is a LAST II study report in Optometry (May 2007) by Richer that discusses macular pigment increases (please see PubMed if interested). To me, this is most profound, take is to take a supplement and to see (and measure (several techniques available, also!!)) the result. And hopefully, have possible acuity increases in this process. Will try to get the full Aleman's paper and Richer's paper. Abstracts leave out too much. So where are we with what you think the zinc level should be? Re wired implants: There is something bothersome to see a neuron axon (dendrite) draped across a silicon substrate tied to a terminal post. Wireless anyone? Other stuff .... later. Don W. > John, > [quoted text clipped - 10 lines] > > So where are we with what you think the zinc level should be? I do not believe one can advise specific individuals on specfic levels for supplements. Individual requirements can vary greatly and change according to their state of health. While I definitely think people with retinal degeneration should be taking supplements like lutein in general I think it is far better to focus on a good diet for the greater part of our nutrition. In particular focus on glutathione enhancing nutrients like sulfurophanes(eg. broccoli is excellent), selenium(brazil nuts), and alpha lipoic acid(asparagus?). You really need to have tests done to determine the best levels for each individual and this is expensive and can be difficult. There is some speculation that macular pigment provides glare tolerance. The pigment protects against the oxidative effects of UV and blue light but increasingly I'm inclined to think that just bright light is an issue. Get sunnies not with UV AND blue light filtering capacity. Wrap around type. You might want to look at caloric restriction, it can have remarkable neuroprotective qualities. In relation to AMD the literature is sparse but other studies indicate retinal protection from the same. However I am not sure the protective value here is that great. I received an email from my friend the other night, their daughter's eyesight has stabilised since starting the regime. Hopeful, wishful thinking, but given prior to that there was noticeable deterioration occurring it is better than the converse ... . Way too early to tell. If it does work I am going to kick that ophthalmologist's arse. Lazy prick. You might want to look at this. I haven't had time to examine it yet but as a SOD nutrient that shows definite promise. Improving SODs levels is definitely a worthy goal for everyone. http://www.glisodin.org/research.htm John. > Re wired implants: There is something bothersome to see a neuron axon > (dendrite) draped across a silicon substrate tied to a terminal post. [quoted text clipped - 3 lines] > > Don W. Don, We just received a bucket of studies from the principle researcher in the Blue Mountains study. Her suggestion, and I tend to agree with it, is that zinc is protective. Understand that drusen and lipofuscin contains all sorts of things, even amyloid. The problem is failure of phagocytosis via cd 36 at the RPE and additionally insufficient lysosomal degradation. Keep the focus on Lutein and zeaxanthin. John. > John, > [quoted text clipped - 18 lines] > > Don W. John, I'm NOT disagreeing with you AT ALL. However, let me reiterate something that I implied earlier; inferential statistics are concerned with the estimation of POPULATION PARAMETERS. They, pretty much literally, have NOTHING to say about individuals, and individuals are what medicine (perhaps as opposed to epidemiology) is about. Just something to think about, Bro. Ask yourself this (not able to "leave it alone"), what does the "mean response" tell you, and what are the problems with this measure. Your Friend, G. > Don, > [quoted text clipped - 29 lines] >> >> Don W. Thanks Glen but. I'm so cynical I make Chomsky sound like a PR man for Halliburton. I've developed a different approach to all this. Had to when looking at the research re Stargardt. Basically I look for synergies across epidemiological, physiological, cellular, and hopefully biochemical studies. Damn sight better than those bloody useless Cochrane reports, a 'gold standard'of clinical practice. Note I what I mentioned to Don earlier in that post: I do not believe one can advise specific individuals on specfic levels for supplements. Individual requirements can vary greatly and change according to their state of health. This is a big problem with health reporting. A few years ago, before my vision collapsed(itself instructive lesson in the follies of clinicians, they were looking in the wrong place) I was invited to help prepare material for a health related website. As I ploughed through the literature I became increasingly concerned about all this health news. I abandoned that project but will pick it up again. With an entirely different focus. I'm currently teaching myself web page design so I can use up the free web space available through my ISP. A rather different focus: I'm going to have a section entitled: "The Inconvenient Truth about Health News". Too much health reporting and nutritional advice is just crap. As much as I dislike naturopathy I'll grant them this: they do treat their patients like individuals, they do tailor their therapies to the individual not the latest pamphlet from the drug company or editorial from a medical journal. Methods are just methods and should never be a substitute for logic. A while ago I posted this on a nutrition forum: I do have some sympathy with Monty's view but the real problem is this: we're individuals, individual nutritional requirements can vary manyfold. Most studies are statistical based, most people simply don't understand how shoddy statistical analyses can be. Experiment with diet, find out what works for you, don't obsess about individual pieces of research otherwise you'll go mad. When it comes to nutrition everyone likes to be an expert about what I call the "statistical human being". Said creature does not exist. You do, find out what works for you. Couple of days ago I posted this on another forum. The data on obesity isn't as clear cut as they would have us believe. You get used to this with medical reporting, always changing their minds. When I was a kid, eat meat, lots of red meat, its good for you. Then there came the 'epidemic' of heamachromatosis(iron overload). Then, don't eat fat, eat carbs, then there came the diabetes epidemic(fat is not that bad you know), prior to that they insisted sugar caused diabetes. Now the dumbass food pyramid, now they have everyone playing suduko to ward off dementia(stupid idea, it is *new* intellectual activities that make the difference), and just today a report of massive vitamin D deficiency rates in this sunburnt country because they kept telling us to stay out of the sun, the dumbasses. Then they wonder why people stop listening . . ----------- Hunter S. Thompson once quipped about life, "Still not weird enough for me." Idiot, it isn't weird, it is just plain stupid. The world has gone silly with tidal waves of useless and all too often dangerous information. Which is why I occasionally lament: I should have been a pair of ragged claws Scuttling across the floors of silent seas TS Eliot. Nonetheless worth the effort, there are gems to be learnt but these are hard won. If you keep in mind all the hazards lurking about in the literature it can be possible to sort the wheat from the chaff. It's just bloody hard work and there is no getting away from that. Insight can be alienating. Thanks for your help Glen, I've always appreciated it. John. > John, > I'm NOT disagreeing with you AT ALL. However, let me reiterate something [quoted text clipped - 41 lines] >>> >>> Don W. John, Regarding "Health News". I did know someone that did carry wet laundry (many years ago) from the basement to the attic clothes lines (winter, no drier in that era, up 3 flights of stairs). The "conventional health wisdom" then was that short spurts of energy expendature was "hard on the heart". When they moved to a retirement community, they could hear ambulance sirens all about them, wondering what all that was about, coming for the cardiac cases. But never to their house. Turns out, years later, the conventional wisdom was that short spurts of workout were ok. X years later, though. In ARMD, I have not seen any studies that tie down the level of cardiac fitness with disease slowing. And I don't see too many Rx's saying to increase fitness. How come, hard to measure? Don W.
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